ArticleThe Journal of antimicrobial chemotherapy2026
Preclinical evaluation of epetraborole in the hollow fibre system model of Mycobacterium abscessus lung disease.
Article in The Journal of antimicrobial chemotherapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers, 1 of them a synthesis that pooled it.
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3 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Systematic and quantitative analyses of hollow fiber model ofMicrobiology spectrum · 2026Pooled it
- Sulbactam-durlobactam plus ceftriaxone dosing and novel treatment regimens forAntimicrobial agents and chemotherapy · 2026Article
- Eravacycline pharmacokinetics/pharmacodynamics in the hollow fiber system model ofMicrobiology spectrum · 2026Article
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6 authors.
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Abstract
backgroundIn patients with Mycobacterium abscessus (MAB) lung disease (LD), guideline-based therapy (GBT) achieves sputum culture conversion in only 20-35% of patients. The poor efficacy is reflected in the hollow fibre model system for MAB-LD (HFS-MAB), where GBT drugs' maximal microbial kill (Emax) below day 0 burden (B0) were amikacin 3 colony-forming units (cfu)/mL, clarithromycin-cefoxitin-amikacin (GBT) 17 cfu/mL, imipenem 20 cfu/mL, and tigecycline 24 cfu/mL.
methodsWe tested the bacterial leucyl-tRNA synthetase (LeuRS) inhibitor, epetraborole, for MICs in 59 MAB isolates, and with seven epetraborole exposures in the HFS-MAB over 21 days. Data were analysed using the inhibitory sigmoid Emax model for microbial kill, and a quadratic function for resistance. Monte Carlo experiments (MCE) were performed to identify the optimal epetraborole dose for the clinic.
resultsThe epetraborole MIC50 was 0.125 mg/L, and the MIC90 was 0.25 mg/L. Epetraborole killed 253 cfu/mL below B0. However, epetraborole microbial effect was terminated by antimicrobial resistance, in an exposure-dependent fashion. Whole genome sequencing revealed concentration-dependent generation of resistance-associated LeuRS mutations, including novel mutations such as Asp433Val, Arg324Ser, and Phe310Cys. The exposure mediating 80% of Emax (EC80) was an AUC0-24/MIC = 202.73. In MCE 750 mg twice daily achieved EC80 in 95.6% and 79.2% of virtual patients for intravenous versus oral administration, respectively.
conclusionEpetraborole microbial kill is the best, thus far, achieved in the HFS-MAB, more than two times omadacycline's 123 cfu/mL below B0. We propose to test a novel combination regimen of epetraborole plus omadacycline plus a β-lactam versus GBT first in the HFS-MAB, followed by clinical trials.
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